Recurrent ocular herpes simplex virus type 1 (HSV-1) infection is a major cause of viral induced blindness. Using the rabbit, we have for the first time in any animal model demonstrated a vaccine and adjuvant combination that produces a statistically significant therapeutic effect against recurrent ocular HSV-1 shedding. This was done using MF59+MTP-PE as adjuvant, expressed and highly purified HSV-2 glycoproteins gD2+gB2 as antigens, and a local periocular route of inoculation. We plan to (1) maximize the therapeutic efficacy by using homologous type I glycoprotein rather than type 2 glycoprotein in the vaccine; (2) determine if systemic inoculation can be substituted for periocular (subconjunctival) vaccination; and (3) alter the adjuvant to a form that might be more effective and that is expected to be approved for human use. Both reduced recurrent corneal disease and reduced spontaneous shedding will be used as endpoints. Our specific aims include: 1. Determine the importance of type specific (HSV-1 versus HSV-2) glycoprotein for local ocular vaccination in therapeutic protection against HSV-1 ocular shedding in rabbits. Our previous experiments employed HSV-2 glycoproteins as a vaccine against HSV-1 recurrence. Homotypic HSV-1 glycoprotein should be more efficacious. 2. Confirm that local periocular vaccination is required for therapeutic efficacy against HSV-1 ocular recurrence. We will determine if periocular vaccination is absolutely required, or whether systemic vaccination might provide similar effectiveness. 3. Demonstrate that the MF59+MTP-PE liposome formulation is as efficacious (or even more efficacious) a vaccine adjuvant against recurrent HSV-1 ocular disease than the original MF59+MTP-PE formulation. The standard MF59+MTP-PE formulation is not well tolerated in humans. However, when incorporated into a liposome formulation MF59+MTP-PE is extremely well tolerated in humans and has also been shown to retain its effectiveness as an adjuvant in guinea pigs.